NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 11, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004017500.1

Allele description [Variation Report for NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr)]

NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr)

HGVS:

NC_000019.10:g.11102739G>A
NG_009060.1:g.18359G>A
NM_000527.5:c.266G>AMANE SELECT
NM_001195798.2:c.266G>A
NM_001195799.2:c.190+2394G>A
NM_001195800.2:c.266G>A
NM_001195803.2:c.266G>A
NP_000518.1:p.Cys89Tyr
NP_000518.1:p.Cys89Tyr
NP_001182727.1:p.Cys89Tyr
NP_001182729.1:p.Cys89Tyr
NP_001182732.1:p.Cys89Tyr
LRG_274t1:c.266G>A
LRG_274:g.18359G>A
LRG_274p1:p.Cys89Tyr
NC_000019.9:g.11213415G>A
NM_000527.4:c.266G>A
P01130:p.Cys89Tyr
c.266G>A

Protein change:

C89Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001674; UniProtKB: P01130#VAR_005309; dbSNP: rs875989894

NCBI 1000 Genomes Browser:

rs875989894

Molecular consequence:

NM_001195799.2:c.190+2394G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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PubChem Substance
DNAAF3-AS1[gene] (400)
ClinVar
PREDICTED: Homo sapiens DNAAF3 antisense RNA 1 (DNAAF3-AS1), transcript variant ...
PREDICTED: Homo sapiens DNAAF3 antisense RNA 1 (DNAAF3-AS1), transcript variant X4, ncRNA
gi|2217502238|ref|XR_007089260.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847784	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Oct 11, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10559517, 16250003, 17142622, 17094996, 27783906, 9259195, 19837725, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847784

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Oct 11, 2019)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia.

Graham CA, McClean E, Ward AJ, Beattie ED, Martin S, O'Kane M, Young IS, Nicholls DP.

Atherosclerosis. 1999 Dec;147(2):309-16.

PubMed [citation]

PMID:: 10559517

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Cys89Tyr variant in LDLR has been reported in the heterozygous state in 7 individuals with hypercholesterolemia and segregated with disease in 1 affected individual (Day 1997, Graham 1999, Fouchier 2005, Humphries 2006, Tosi 2010, Wald 2016). It was also identified in the compound heterozygous state with a deletion of exons 16 and 17 in a child with a severe presentation. His father carried the p.Cys89Tyr variant and also had hypercholesterolemia (Tosi 2007). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional variants involving this codon (p.Cys89Trp, p.Cys89Arg, and p.Cys89Gly) have been identified in individuals with hypercholesterolemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PM2, PM3, PS4_Moderate, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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